View of CONVENTIONAL THERAPY OF PSORIATIC ARTHRITIS: EVIDENCE-BASED REVIEW

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Corresponding author:

Neil J McHugh, MD

Royal National Hospital for Rheumatic Diseases Upper Borough Walls, Bath, BA1 1RL E-mail: neil.mchugh@rnhrd-tr.swest.nhs.uk

CONVENTIONAL THERAPY OF PSORIATIC ARTHRITIS:

EVIDENCE-BASED REVIEW

N.J. MCHUGH¹, E.R. SORIANO²

1Royal National Hospital for Rheumatic Diseases, Upper Borough Walls, Bath, UK;

2Hospital Italiano de Buenos Aires, Argentina

INTRODUCTION

Psoriatic arthritis (PsA) is an inflammatory synovitis and/or enthesitis that affects about 30% of individu- als with psoriasis. The prevalence of PsA is likely to be around 0.1-0.3% (1). PsA has been defined as an inflammatory arthritis associated with psoriasis, usually seronegative for rheumatoid factor (2). Histori- cally five subgroups were defined (3), although it is now realised that patients change subgroups over time with disease progression (4). Newer classification criteria have been proposed recently (5).

In its most severe form PsA causes widespread de- structive joint disease and/or ankylosis. Conven- tional drug treatments have included anti-inflammatory agents, corticosteroids and disease-modifying drugs used for rheumatoid arthritis, although the evidence-base for their effectiveness in PsA is not well established. Patients reaching a referral centre for arthritis are likely to have progressive spinal and peripheral joint disease (4, 6-8) despite use of conventional disease modifying an- tirheumatic drugs (DMARDs). Erosive and de- forming arthritis occurs in 40%-60% of hospital-

based PsA patients and is progressive from within the first year of diagnosis (4, 6, 8). Therefore, re- cent international efforts have been made to review the evidence for efficacy and toxicity of available agents for treating PsA, as a prerequisite for de- veloping treatment guidelines (9).

Herein, we summarise some of the evidence that has been compiled using the appropriate methods for literature review, evidence weighting and treatment recommendations. Our summary is confined to conventional treatments for PsA, including peripheral arthritis (10), axial disease (11), enthesopathy (12) and dactylitis (13). More detailed ac- counts of the outcome methods used and method- ology are published elsewhere (9-13).

NON-STEROIDAL ANTI-INFLAMMATORY AGENTS

Non-steroidal anti-inflammatory drugs (NSAIDs) are usually the first choice of agents in the treatment of PsA and have demonstrated efficacy in re- lieving symptoms (14-17).

The usual caveats apply in taking caution in patients at risk of gastrointestinal, renal and cardio- vascular toxicity.

There is no evidence that NSAIDs slow disease progression, although continued use may slow radiological progression of ankylosing spondylitis SUMMARY

Psoriatic arthritis is a heterogeneous condition, the pattern of which is determined by any combination of pathology affecting peripheral joints, the enthesis and the spine. There is a paucity of evidence for most of the conventional agents used to treat psoriatic arthritis, with many of them being used on the basis of experience in rheumatoid arthritis. Here- in, we summarise the evidence compiled relating to effectiveness of treatment for various manifestation of PsA. For those patients with progressive forms of arthritis who may benefit from intervention of newer biological therapies, the continued use of conventional therapy needs ever increasing scrutiny.

Key words: Psoriatic arthritis, psoriasis, therapy

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82 N.J. McHugh, E.R. Soriano

(18). There are occasional reports of NSAIDs caus- ing flare of skin psoriasis (19).

CORTICOSTEROIDS

There are no RCTs of systemic or intra-articular corticosteroids in PsA. Systemic corticosteroids are occasionally required for severe flares of arthritis.

Discontinuation of corticosteroids has been linked to rebound of skin psoriasis. On the other hand, the use of intra-articular corticosteroid injection is widespread and felt to be a valuable form of treatment, especially for persistent mono or oligoarthritis.

SULPHASALAZINE

Sulphasalzine is often the first disease modifying drug used in PsA. A systematic review (20, 21) found six studies comparing sulphasalazine to placebo for PsA (22-27). Overall there is evidence for efficacy of sulphasalazine in improving clinical symptoms of peripheral joint disease although the effect is no more than modest. Also up to a third of patients may suffer adverse events such as gastrointestinal intolerance, dizziness or liver toxicity. There is no evidence that sulphsalazine prevents radiographic progression. Sulphsalazine appears to be ineffective for the treatment of axial disease (28), and studies are inconclusive for enthesitis and dactylitis.

METHOTREXATE

Methotrexate is commonly used as a disease modifying drug in PsA and may also be effective for skin psoriasis, although there is a lack of controlled studies in either condition (29, 30). Liver toxicity may be more frequent with methotrexate in PsA than in rheumatoid arthritis (31).

Histopathological findings may not be predicted by liver function tests (32, 33). However, there is some evidence that levels of amino-terminal propeptide of type III procollagen can be used as a guide as to the necessity of a liver biopsy in patients requiring methotrexate longterm (34).

CYCLOSPORIN

Cyclosporin is an effective agent for skin psoriasis but less often used for PsA.

There have been two studies comparing cyclosporin to other agents used in PsA, suggesting superior efficacy to sulphaslazine (35), similar efficacy to methotrexate (36), but overall greater toxicity. Re- nal toxicity in particular is a major limitation.

LEFLUNOMIDE

Leflunomide (Arava - Aventis) is an isoxaol deriv- ative that in its active form inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme essential for the de-novo synthesis of pyrimidines. Since ac- tivated lymphocytes require a large pyrimidine pool, leflunomide preferentially inhibits T cell ac- tivation and proliferation. As T cells play a pivotal role in the immunopathogenesis of both skin psoriasis and PsA, leflunomide is an obvious candidate agent for use in these conditions. In addition, leflunomide has been shown to be effective in rheumatoid arthritis.

Initial uncontrolled studies suggested that leflunomide was effective in PsA. A further randomised control trial involving 190 patients with active arthritis (at least three tender and three swollen joints) demonstrated efficacy in improving clinical symptoms of arthritis and secondary measures including disability and skin psoriasis (37). Patients were randomised to receive either leflunomide (100mg/day for three days followed by 20mg/day) or placebo with outcomes measured at 4 weeks.

Leflunomide was significantly superior to placebo in the number of patients to respond as measured by the PsARC (Psoriatic arthritis response criteria)(59% (95% CI 48-70) versus 30% (95% CI 21- 40)) and in each individual component of the PsARC. Leflunomide was also significantly better than placebo in improving disability and quality of life as measured by the HAQ (Health Assessment Questionaire) and the DQLI (Dermatology Quali- ty of Life Index). Improvement in skin psoriasis as measured by a PASI (Psoriasis Area and Severity Index) score was also significantly better with leflunomide. Compared to the placebo group, a greater proportion of patients in the leflunomide group experienced a ?50% reduction in PASI scores (PASI 50; 18.9% vs 30.4%; p=0.050) and

?75% reduction in PASI scores (PASI 75; 7.8% vs 17.4%; p = 0.048) from baseline.

In the above study serious adverse events were more common in the leflunomide-treated group (13.5%) than in the placebo-treated group (5.4%).

The most frequent adverse events with leflunomide

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Conventional therapy of psoriatic arthritis: evidence-based review 83

were diarrhoea (24%), increased liver enzymes (12.5%), flu-like syndrome (12.5%) and headache (11.5%). Three leflunomide treated patients and 1 placebo treated patient were withdrawn from the study because of elevated transaminase levels, which returned to normal during follow up. No cas- es of severe liver toxicity were observed. The lev- el of unwanted effects appears to be similar to that experienced in rheumatoid arthritis patients treated with leflunomide.

MYCOPHENOLATE

Mycophenolate mofetil (MMF) inhibits inosine monophosphate and the subsequent de novo gua- nine synthesis necessary for DNA replication in lymphocytes but not neutrophils. MMF is most commonly used to prevent organ graft rejection and is gaining more widespread use for maintain- ing disease remission in a range of autoimmune disorders. Small studies in PsA have been promis- ing (38). MMF is rapidly converted to its active metabolite mycophenolic acid, that may have less gastrointestinal side effects than MMF.

OTHER DISEASE MODIFYING AGENTS Most of the disease modifying drugs used for rheumatoid arthritis are occasionally used for PsA, although there are very few properly controlled studies. Gold salts (auranofin and sodium thioma- late) are probably no more effective than placebo.

Azathioprine may be effective but larger trials are needed. Antimalarials should be avoided as they have been associated with severe exacerbations of psoriasis (39), and there is no convincing evidence of effectiveness for PsA. The use of combination therapy with traditional disease modifying agents has not been the subject of any well-designed prospective study in PsA.

CONCLUSIONS

The advent of effective biological agents for the treatment of PsA has brought to attention the rela- tive lack of evidence for conventional therapies.

Conventional disease modifying agents should not be disregarded simply because they have been un- der-evaluated in PsA, and experience with their use in rheumatoid arthritis is generally reassuring in

terms of long-term safety. Sulphasalazine has been studied more than others and has no more than modest efficacy, methotrexate needs further evalu- ation, and cyclosporin is limited by toxicity.

Leflunomide is a useful addition to the list of disease modifying agents and will probably become more commonly used before consideration is giv- en to a biologic agent.

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